A synDNA vaccine delivering neoAg collections controls heterogenous, multifocal murine lung and ovarian tumors via robust T cell generation

Abstract

Neoantigens are tumor-specific antigens that arise due to somatic mutations in the DNA of tumor cells. They represent ideal targets for cancer immunotherapy since there is minimal risk for on-target, off-tumor toxicities. Additionally, these are foreign antigens that should be immunogenic due to lack of central immune tolerance. Tumor neoantigens are predominantly passenger mutations, which do not contribute to tumorigenesis. In cases of multi-focal or metastatic tumors, different foci can have significantly different mutation profiles. This suggests that it is important to target as many neoantigens as possible to better control tumors and target multi-focal tumors within the same patient. Herein, we report a study targeting up to 40 neoantigens using a single DNA plasmid. We observed significant plasticity in the epitope strings arranged in the vaccine with regard to immune induction and tumor control. Different vaccines elicited T cell responses against multiple epitopes on the vaccine string and controlled growth of multifocal, heterogeneous tumors in a therapeutic tumor challenge. Additionally, the multi-epitope antigens induced long-term immunity and rejected a tumor re-challenge several weeks after the final vaccination. These data provide evidence that DNAencoded long antigen strings can be an important tool for immunotherapeutic vaccination against neoantigens with implications for other in vivo-delivered antigen strings.

Neoantigen cancer vaccine augments anti-CTLA-4 efficacy

“…The creation of a successful therapeutic protocol that combines ICI and NCV is currently a work in progress. The induction of multi-epitopic and multi-functional immune responses by NCV was shown to be relevant in the MC38 tumor model 15 and other tumor models 31 , 41 . Here we extended this concept and explored the strength of DNA-EP platform confirming the immunogenicity of neoantigen previously used in other delivery systems or in the form of shorter coding sequencing (Tables 1 and 2 ).…”

Nucleic acid‐based vaccine for ovarian cancer cells; bench to bedside

“…Since the development of multiepitope T cell memory appears to have an advantage over tumor recurrence, encoding several neoantigens-in this example, by a DNA vaccine-can be a beneficial tool for targeting heterogeneous multifocal or metastatic cancers. 104 To investigate the theory that ovarian cancer cells will express more class I MHC and cancertestis antigens (CTA) when their DNA methylation is reduced. 105 This will enhance the cells' capacity to be recognized by antigenreactive CD8+ T cells.…”

Neoantigens in precision cancer immunotherapy: from identification to clinical applications

“…DNA has also used to produce neoantigen vaccines. Researchers have shown that synthetic DNA vaccines – recombinant plasmids that can produce neoantigens – can generate robust T cell responses in mice [85–87] . Another study indicated that combining DNA vaccination with anti-PD-1 therapy can achieve a synergistic effect in controlling tumor growth [88] .…”

“…Researchers have shown that synthetic DNA vaccinesrecombinant plasmids that can produce neoantigenscan generate robust T cell responses in mice. [85][86][87] Another study indicated that combining DNA vaccination with anti-PD-1 therapy can achieve a synergistic effect in controlling tumor growth. [88] Their data suggest that a combination strategy of immunotherapies may bring about unexpected benefits.…”